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WO1999002492A1 - Formes cristallines d'intermediaires a chaine laterale antibiotiques - Google Patents

Formes cristallines d'intermediaires a chaine laterale antibiotiques Download PDF

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Publication number
WO1999002492A1
WO1999002492A1 PCT/US1998/014036 US9814036W WO9902492A1 WO 1999002492 A1 WO1999002492 A1 WO 1999002492A1 US 9814036 W US9814036 W US 9814036W WO 9902492 A1 WO9902492 A1 WO 9902492A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystalline
pyrrolidinyl
mercapto
cis
carbonyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1998/014036
Other languages
English (en)
Inventor
Karel M. J. Brands
Ronald B. Jobson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9800463.3A external-priority patent/GB9800463D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Priority to EP98933212A priority Critical patent/EP0998457A4/fr
Priority to CA002294341A priority patent/CA2294341C/fr
Priority to JP50883899A priority patent/JP3378021B2/ja
Priority to AU82920/98A priority patent/AU736136B2/en
Publication of WO1999002492A1 publication Critical patent/WO1999002492A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • Crystalline forms of intermediates for carbapenem antibiotics are desirable from a stability and purity standpoint. These compounds facilitate the synthesis of carbapenem antibiotics on a commercial scale.
  • crystalline forms of the compound 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl)carbonyl]-amino] benzoic acid have been discovered and characterized.
  • Crystalline 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl)carbonyl]-amino]benzoic acid and pharmaceutically acceptable salts and solvates thereof are disclosed.
  • the compounds can generally be synthesized taking into account the disclosure of U. S. Patent No. 5,478,820 granted on December 26, 1995. This patent does not disclose the side chain in crystalline form.
  • Figure 1 is an X-Ray Powder Diffraction pattern of Compound I, in unsolvated form
  • Figure 2 is an X-Ray Powder Diffraction pattern of Compound I as the 1-butanol solvate
  • Figure 3 is an X-Ray Powder Diffraction pattern of Compound I, as the acetic acid solvate.
  • the compound has the following structural formula:
  • the salt form of the compound can be protonated as shown in the following:
  • X represents a negatively charged counterion.
  • the salt forms can also be present in the form of a solvate.
  • the crystalline forms of the compound are characterized below by virtue of their X-Ray Powder Diffraction (XRPD) patterns.
  • the XRPD patterns were collected on a Philips APD 3720 automated powder diffractometer.
  • the x-ray generator employed a copper target, an accelerating potential of 45 kV and a filament emission of 40 mA. Diffraction patterns were collected from 2°C to 40°C.
  • the hydrochloride salt of the compound (unsolvated material) was characterized as having an XRPD pattern at 5.5, 5.3, 4.9, 4.3, 4.1, 3.9, 3.8, 3.7, 3.6, 3.3, 3.2, 2.9, 2.6 and 2.3 angstroms. More complete XRPD data pertaining to the compound is shown below in Table 1.
  • Step size sample time 0.015 deg, 0.20 s, 0.075 deg/s
  • the hydrochloride salt 1-butanol solvate was shown to exhibit patterns such as the ERPD pattern shown as Figure 2. Characteristic D-spacings are 14.6, 7.3, 5.6, 4.9, 4.2, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.3, 3.0 and 2.9 Ang. More complete XRPD data pertaining to the solvate is shown below in Table 2.
  • Step size sample time 0.015 deg, 0.20 s, 0.075 deg/s
  • Solid material which was exposed to acetic acid was characterized as having an XRPD pattern at 5.4, 5.3, 5.1, 4.2, 3.8, 3.6, 3.4, 3.1, 2.7 and 2.6 angstroms. More complete XRPD data pertaining to the solvate is shown below in Table 3.
  • Peak position criterion Top of smoothed data Cryst peak width range 0.00-2.00 deg
  • the crystalline compound of the present invention is useful in various pharmaceutically acceptable salt forms, for the synthesis of carbapenem compounds that are in turn useful for the treatment of bacterial infections in animal and human subjects.
  • pharmaceutically acceptable salt refers to those salt forms which would be apparent to the pharmaceutical chemist, i.e., those which are substantially non-toxic and which provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion.
  • Other factors, more practical in nature, which are also important in the selection, are cost of the raw materials, ease of crystallization, yield, stability, hygroscopicity and flowability of the resulting bulk drug.
  • the intermediate compound is protonated, and is found in association with a negatively charged counterion, represented by the generic X".
  • a negatively charged counterion represented by the generic X.
  • charge balancing counterion X Representative examples of such counterions are the following: acetate, adipate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate, benzoate, benzenesulfonate, bicarbonate, bisulfate, bromide, citrate, camphorate, camphorsulfonate, carbonate, chloride, digluconate, edetate, edisylate, estolate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycolate, hydroxynaphthoate, 2-hydroxyethanesulfonate, iodide, lactate, lactobionate, malate, maleate, man
  • the preferred form of the crystalline compound is the hydrochloride salt form.
  • the compound can be produced in accordance with the following non-limiting examples.
  • the BOC protected sidechain 1 (prepared according to the teachings of PCT WO97/06154 published on February 20, 1997) was dissolved in 1.5 L of a 1 N solution of dry hydrogen chloride in acetic acid (30 min). Gas evolution was observed and the reaction product slowly crystallized. After filtering, washing (with acetic acid and hexane) and drying 137 g of product was obtained. The crystals contain acetic acid but are not a solvate.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

L'invention concerne un acide 2S-cis-3[[(4-mercapto-2-pyrrolidinyl) carbonyl]-amino]benzoïque cristallin, ainsi que ses sels et ses solvates. L'invention concerne également trois types cristallins différents.
PCT/US1998/014036 1997-07-10 1998-07-07 Formes cristallines d'intermediaires a chaine laterale antibiotiques Ceased WO1999002492A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP98933212A EP0998457A4 (fr) 1997-07-10 1998-07-07 Formes cristallines d'intermediaires a chaine laterale antibiotiques
CA002294341A CA2294341C (fr) 1997-07-10 1998-07-07 Formes cristallines d'intermediaires a chaine laterale antibiotiques
JP50883899A JP3378021B2 (ja) 1997-07-10 1998-07-07 結晶形態の抗菌性側鎖中間体
AU82920/98A AU736136B2 (en) 1997-07-10 1998-07-07 Crystalline forms of antibiotic side chain intermediates

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US5219797P 1997-07-10 1997-07-10
US60/052,197 1997-07-10
GBGB9800463.3A GB9800463D0 (en) 1998-01-09 1998-01-09 Crystalline forms of antibiotic side chain intermediates
GB9800463.3 1998-01-09

Publications (1)

Publication Number Publication Date
WO1999002492A1 true WO1999002492A1 (fr) 1999-01-21

Family

ID=26312922

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/014036 Ceased WO1999002492A1 (fr) 1997-07-10 1998-07-07 Formes cristallines d'intermediaires a chaine laterale antibiotiques

Country Status (5)

Country Link
EP (1) EP0998457A4 (fr)
JP (1) JP3378021B2 (fr)
AU (1) AU736136B2 (fr)
CA (1) CA2294341C (fr)
WO (1) WO1999002492A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002006222A1 (fr) * 2000-07-19 2002-01-24 F. Hoffmann-La Roche Ag Derives de pyrrolidine utilises comme inhibiteurs de l'enzyme de conversion de l'endotheline
WO2010073706A1 (fr) * 2008-12-25 2010-07-01 株式会社カネカ Procédé de production amélioré d'un intermédiaire pour chaîne latérale de carbapénème

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5478820A (en) * 1992-02-04 1995-12-26 Zeneca Ltd. Antibiotic compounds

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999002531A1 (fr) * 1997-07-09 1999-01-21 Merck & Co., Inc. Procede de synthetisation d'intermediaires de carbapenem a chaine laterale

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5478820A (en) * 1992-02-04 1995-12-26 Zeneca Ltd. Antibiotic compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0998457A4 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002006222A1 (fr) * 2000-07-19 2002-01-24 F. Hoffmann-La Roche Ag Derives de pyrrolidine utilises comme inhibiteurs de l'enzyme de conversion de l'endotheline
US6541638B2 (en) 2000-07-19 2003-04-01 Hoffman-La Roche Inc. Pyrrolidine derivatives
WO2010073706A1 (fr) * 2008-12-25 2010-07-01 株式会社カネカ Procédé de production amélioré d'un intermédiaire pour chaîne latérale de carbapénème
CN102264744A (zh) * 2008-12-25 2011-11-30 株式会社钟化 碳青霉烯侧链中间体的改良制造方法

Also Published As

Publication number Publication date
JP3378021B2 (ja) 2003-02-17
JP2002504157A (ja) 2002-02-05
AU736136B2 (en) 2001-07-26
EP0998457A4 (fr) 2010-03-10
CA2294341A1 (fr) 1999-01-21
EP0998457A1 (fr) 2000-05-10
AU8292098A (en) 1999-02-08
CA2294341C (fr) 2007-09-25

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